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Autophagy, Apoptosis and Cell Cycle Checkpoints in Deregulated Cellular Plasticity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2025) | Viewed by 2135

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Center for Research and Development of the Morphological and Genetic Studies of Malignant Pathology, “Ovidius” University of Constanta, 145 Tomis Blvd., 900591 Constanta, Romania
Interests: inflammatory disorders such as sarcoidosis, IBD (colitis, Crohn’s disease), diverticulitis, or prostate cancer biomarkers; regulation pathways; intratumor heterogeneity; regulatory T cells (Tregs); natural killer T (NKT) cells
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Special Issue Information

Dear Colleagues,

Cell-death escape is important in targeting cancer therapies involving molecular events caused by major apoptotic pathways, including the death receptor pathway (extrinsic) and the mitochondrial pathway (intrinsic). Genetic alterations in the cell proliferation/apoptosis regulation pathways in cancer development suggest an autophagy–apoptosis network. In tumor progression, autophagy pathway deregulation acts as a safeguard mechanism in uncontrolled cell growth restriction, being a protective mechanism against apoptosis. Uncontrolled cellular growth and cell death due to defects in the cell cycle are usually responsible for the development of most of the cancers. The progression of the cell cycle is under many regulatory complex mechanisms influenced by exogenous factors that control the cell cycle at the G1, S, and G2 checkpoints. Most human’s cancers present defects in these checkpoints, making them interesting targets for chemoprevention. Cellular plasticity represents a cell’s ability to switch dynamically and reversibly from one phenotypic state to another. Deregulated cell plasticity is implicated in cancer initiation, progression, metastasis, and therapy resistance in various cancer types. Genetic and epigenetic mechanisms and cell-extrinsic factors such as inflammation, microenvironment, and therapeutic stress can induce cellular plasticity.

In this Special Issue, I invite researchers to present original studies and state-of-the-art reviews about regulation pathways and checkpoints implied in cell death, the cell cycle, and cell plasticity to target cancer therapies.

Dr. Elena Matei
Guest Editor

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Keywords

  • autophagy
  • apoptosis
  • cell cycle
  • cell plasticity
  • regulation pathways
  • checkpoints

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Published Papers (1 paper)

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Research

18 pages, 4707 KB  
Article
Aging Rewires Neuronal Metabolism, Exacerbating Cell Death After Ischemic Stroke: A Hidden Reason for the Failure of Neuroprotection
by Matvey Vadyukhin, Vladimir Shchekin, Petr Shegai, Andrey Kaprin and Grigory Demyashkin
Int. J. Mol. Sci. 2026, 27(1), 81; https://doi.org/10.3390/ijms27010081 - 21 Dec 2025
Viewed by 1749
Abstract
Aging profoundly modifies neuronal responses to ischemia. We aimed to define age-dependent features of neuronal metabolism and cell death after ischemic stroke by assessing NeuN, NSE, and Caspase-3 in human cortical neurons and by comparing transcriptional activity within PI3K/Akt/mTOR and PI3K/Akt/FOXO3a pathways across [...] Read more.
Aging profoundly modifies neuronal responses to ischemia. We aimed to define age-dependent features of neuronal metabolism and cell death after ischemic stroke by assessing NeuN, NSE, and Caspase-3 in human cortical neurons and by comparing transcriptional activity within PI3K/Akt/mTOR and PI3K/Akt/FOXO3a pathways across age groups. The aim of this study was to determine age-dependent features of neuronal metabolism and cellular degradation in ischemic stroke based on immunohistochemical assessment of NeuN, NSE, and Caspase-3 markers in human cerebral cortex neurons, as well as to conduct a comparative analysis of gene expression in the PI3K/Akt/mTOR and PI3K/Akt/FOXO3a signaling pathways involved in the regulation of neuronal survival and apoptosis. For the investigation, frontal cortex autopsies from patients with ischemic stroke (n = 154; “young”, “middle” and “elderly”; death ≤7 days post-onset) were examined. Histology (hematoxylin–eosin) and Nissl staining were used for morphology and neuron counts. Multiplex immunofluorescence (NeuN, NSE, Caspase-3) quantified metabolically active and apoptotic neurons, and the percentage of Caspase-3+ among NeuN+ cells was calculated. qRT-PCR measured PIK3CA, AKT2, MTOR, and FOXO3A expression in the infarct border zone. Based on our results, neuronal density and NeuN/NSE expression declined with aging, and the fraction of Caspase-3+ among NeuN+ neurons in the penumbra rose (young 42%, middle 82%, elderly 89%). Morphologically “intact” penumbral neurons frequently lacked NeuN/NSE, revealing covert dysfunction. Young brains showed balanced activation of PI3K/Akt/mTOR and PI3K/Akt/FOXO3a, whereas elderly brains exhibited reduced Akt/mTOR activity with FOXO3A predominance, consistent with pro-apoptotic, inflammatory, and dysregulated autophagic signaling. Thus, aging markedly reduces neuronal metabolic activity and increases apoptotic death in the infarct border zone after ischemic stroke. In older patients, there is an almost complete loss of NeuN and NSE expression in penumbral neurons with robust activation of the caspase cascade, whereas younger patients retain a pool of metabolically active neurons. Age-dependent dysregulation of PI3K/Akt signaling—characterized by FOXO3a hyperactivation and mTOR suppression—further promotes apoptosis and dysregulated autophagy. These changes likely underlie the limited efficacy of standard neuroprotection in ischemic stroke and support the need for age-tailored neurotropic therapy aimed at enhancing pro-survival pathways within the infarct border zone. Full article
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